The Staudt laboratory has conducted RNA interference genetic screens for genes required for the proliferation and/or survival of human cell lines representing various subtypes of lymphoma and multiple myeloma. In diffuse large B cell lymphoma (DLBCL), previous work in the Staudt laboratory demonstrated that the anti-apoptotic NF-kB pathway is constitutively active in the activated B cell-like (ABC) subtypes of DLBCL but not the germinal center B cell-like (GCB) subtype of DLBCL, but the mechanisms underlying this abnormal signaling were enigmatic. The laboratory therefore conducted an RNAi screen in ABC and GCB DLBCL cell lines, searching for shRNAs that were selectively toxic for ABC DLBCL cells. This effort revealed that a signaling complex comprised of CARD11, MALT1, and BCL10 is required for the survival of ABC but not GCB DLBCL cell lines. In normal lymphocytes, this CARD11 complex engages the NF-kB pathway during antigen receptor signaling. The Staudt laboratory demonstrated that this signaling complex is responsible for the constitutive activation of the NF-kB pathway in ABC DLBCLs. In a recent RNA interference screen we identified several shRNAs targeting casein kinase 1A1 (CK1&amp;#945;) that were toxic for ABC but not GCB DLBCL cell lines. Since this phenotype resembled the toxicity profile of CARD11 shRNAs, we suspected that CK1&amp;#945;might be a new component of the CBM signaling pathway. Indeed, CK1&amp;#945;knockdown decreased IKK kinase activity and NF-kB target gene expression, and CK1&amp;#945;colocalized with CARD11 in ABC DLBCL cell lines. Fortuitously, Mike Lenardo's laboratory in NIAID separately identified CK1&amp;#945; as a binding partner of CARD11 in a mass spectrometry-based screen. Collaborative experiments revealed the essential role of CK1&amp;#945;in T cell receptor activation of the NF-kB pathway. Biochemically, CK1&amp;#945;was required for the recruitment of IKK to the CBM complex. Interestingly, T cells reconstituted with a CK1&amp;#945;mutant that was defective in kinase activity provided a greater NF-kB stimulus than did wild type CK1&amp;#945;, demonstrating that CK1&amp;#945;has both positive and negative influences on the CBM pathway. The negative effect of CK1&amp;#945;was due to its phosphorylation of CARD11 on serines in its "linker" domain, causing CARD11 to be destabilized. This negative feedback loop involving CK1&amp;#945;was analogous to the negative regulation of the CBM complex caused by inhibitory phosphorylation of BCL10 by IKK. CK1&amp;#945;emerged from this study as a new component of the CBM, demonstrating the power of unbiased RNA interference screens to uncover overlooked aspects of cellular signaling. A recent RNAi screen uncovered a crucial dependency of multiple myeloma cells on IRF4, a lymphoid-restricted transcriptional factor that is required for both lymphocyte activation and for plasmacytic differentiation. IRF4 knockdown by RNAi was toxic to 10 different myeloma cell lines representing many of the known genetic subtypes of this cancer. Of note, IRF4 is not translocated, amplified or mutated in most cases of multiple myeloma, and thus the dependency of myeloma cells on IRF4 exemplifies a new concept in cancer biology known as non-oncogene addiction. These results establish IRF4 as an important new therapeutic target in this lethal cancer.